US3245988A - Steroid [2, 3-c] furazan compounds and the process for the production thereof - Google Patents

Steroid [2, 3-c] furazan compounds and the process for the production thereof Download PDF

Info

Publication number
US3245988A
US3245988A US350585A US35058564A US3245988A US 3245988 A US3245988 A US 3245988A US 350585 A US350585 A US 350585A US 35058564 A US35058564 A US 35058564A US 3245988 A US3245988 A US 3245988A
Authority
US
United States
Prior art keywords
furazan
reaction
acid
androstano
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US350585A
Other languages
English (en)
Inventor
Ohta Genkichi
Takegoshi Toshio
Onodera Takeshi
Kasahara Akira
Oshima Yasuo
Shimizu Masao
Ueno Katsujiro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Pharmaceutical Co Ltd
Original Assignee
Daiichi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Pharmaceutical Co Ltd filed Critical Daiichi Pharmaceutical Co Ltd
Application granted granted Critical
Publication of US3245988A publication Critical patent/US3245988A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0057—Nitrogen and oxygen
    • C07J71/0063—Nitrogen and oxygen at position 2(3)

Definitions

  • R represents a hydrogen atom or a methyl group and R represents a hydrogen atom or an acyl residue of a hydrocarbon carboxylic acid having less than 16 carbon atoms.
  • the compounds shown by the above formula are androstano(2,3C)furazan derivatives that have a structure in which the steroid nucleus contains a hydroxyl group or an acylated hydroxyl group plus a hydrogen atom or a methyl group at the l7-position of Sea-androstane, and 2- and 3-positions of the steroid are fused to 3- and 4-positions of a furazan nucleus ring, that is, 1,2',5-oxadiazol nucleus ring.
  • acyl group herein means an acyl residue of an organic acid having less than 16 carbon atoms.
  • the organic acid is any acid such as, for example, acetic acid, propionic acid, butyric acid, n-heptanoic acid, n-decanoic acid, palmitic acid, benzoic acid, phenylpropionie acid, cyclohexylpropionic acid, and succinic acid.
  • the 17,8-hydroxyor 17fl-acyloxy-5ot-androstano(2,3- C)furazan compounds of this invention were found to have potent anabolic and weak androgenic activity.
  • the anabolic activity can be estimated by the myotropic activity on immature castrated male rats. For example, the following results were obtained with respect to the activities of representative compounds of this invention.
  • 17/3-hydroxy-17a-methyl-5aandrostano(2,3-C)furazan had 1 to 1.5 times the myotropic and 0.2 to 0.3 times the androgenic activity of testosterone propionate.
  • oral assay it had 5.6 times the myotropic and 0.7 times the androgenic activity of methyltestosterone.
  • l7fi-hydroxy-5a-androstano(2,3-C)furazan had 1.2 to 1.6 times the myotropic and 0.2 times the androgenic activity of testosterone propionate when administered subcutaneously.
  • the anabolic hormone is useful for the treatment of cases which are caused by poor utilization of nitrogen. Generally, however, the anabolic hormone is usually accompanied by androgenic activity and, therefore, shows undesirable side effects.
  • the compounds of this invention can be said to be an extremely desirable anabolic agent because they have excellent anabolic activity and, at the same time, have weak androgenic activity.
  • the following reaction formulas represent the production processes of the novel compounds of this invention:
  • R represents a hydrogen atom or the aforementioned acyl group when succinic anhydride is employed as a dehydrating agent, and represents the aforementioned acyl group when thionyl chloride is employed as a dehydrating agent; and R" represents COCH CH COOH whenR is a hydrogen atom, and succinic anhydride is used as a dehydrating agent, and represents the same as R when R represents the aforementioned acyl group.
  • the designation Acyl represents the same acyl group as defined in regard to R'.
  • R and R are the same representations as defined in the reaction Formula 1, with an alkyl nitrite in the presence of an alkali or an acid.
  • an isoamyl nitrite or the like known as a nitrosating agent, may be employed as an alkyl nitrite.
  • an alkali an alkali alkoxide prepared from an alkali metal and a lower aliphatic alcohol, preferably potassium tertiary butoxide may be employed. When potassium tertiary butoxide is employed as an alkali in the reaction, it is preferable to carry out the reaction in a nitrogen atmosphere in order to prevent air-oxidation.
  • hydrogen chloride is preferably employed as an acid.
  • the compound of the Formula I wherein X represents 0, and R and R are the same representations as defined in the reaction Formula 1, is produced by the method described by R. Camerino et al. in Tetrahedron Letters, p. 554 (1961), and includes tautomeric isomers, any of which can be used without isolation.
  • the reaction of the Formula 1 is a process in which the compound of the general Formula I is reacted with hydroxylamine.
  • an alcohol or an aqueous alcohol as a solvent and to carry out heating at a temperature between room temperature and 100 C. under weak alkaline conditions.
  • an alcohol for example, methanol, ethanol or tertiary butanol is employed.
  • pyridine, potassium acetate, or sodium acetate is employed as a solvent.
  • the reaction of the formula 2 is a process in which ring-closure under dehydration is effected by heating the compound of the general Formula II in the presence of an alkali.
  • it is appropriate to heat the compound of the general Formula II in the presence of an alkali in a solvent that does not disturb the reaction.
  • a solvent water, alcohols, hydro-carbons such as tetralin, and preferably ethylene glycol are employed.
  • alkali alkali hydroxide, alkali carbonate, alkalibicarbonate, ammonia, organic amines such as pyridine and piperidine may be employed, but the use of an alkali hydroxide or an alkali carbonate is preferable.
  • alkalis to 'be used are in liquid form, they also serve as a solvent.
  • the reaction can be carried out at a temperature between 100 C. and 250 C. preferably between 160" C. and 190 C.
  • the reaction can also be performed under increased pressure.
  • the reaction of the Formula 3 is a process in which the 2,3-dihydroxyimino-and rostane compound of the Formula II is ring-closed by the use of a dehydrating agent selected from the group consisting of succinic anhydride and thionyl chloride.
  • a dehydrating agent selected from the group consisting of succinic anhydride and thionyl chloride.
  • succinic anhydride and thionyl chloride
  • the reaction is preferably carried out in liquid sulfur dioxide.
  • thionyl chloride only or thionyl chloride in pyridine is employed, only a small amount of the desired furazan compound is obtained. It is appropriate to carry out the reaction at a temperature between -20 C. and -10 C. and to use as a starting material the compound of the Formula II" wherein R represents an acyl group.
  • the reaction of the Formula 4 is a process in which the compound of the Formula III is acylated with an acylating agent.
  • an acylating agent functional derivatives such as an acid chloride and an acid anhydride of an organic acid having less than 16 carbon atoms, for example, acetic acid, propionic acid, butyric acid, n-heptanoic acid, n-decanoic acid, palmitic acid, benzoic acid, phenylpropionic acid, cyclohexylpropionic acid and succinic acid, may be employed.
  • the reaction is preferably carried out at a temperature between room temperature and 200 C. with or without a solvent that does not disturb the reaction.
  • the aforementioned acid anhydride or acid chloride can be reacted with it to yield the compound of the Formula III. That is, the compound of the Formula III can be obtained by reacting the compound of the Formula III with an alkyl magnesium halogenide such as ethyl magnesium bromide, and then reacting the magnesium compound thus obtained with the aforementioned acylating agent.
  • an alkyl magnesium halogenide such as ethyl magnesium bromide
  • Example 3 A mixture of 2.35 g. of 2-hydroxyimino-17/8-hydroxy- 5a-androstan-3-one, 0.7 g. of hydroxylamine hydrochloride, 5 ml. of pyridine and 100 ml. of methanol was heated under reflux for one hour. After the resulting product was cooled, separated crystals were filtered. The mother liquor was condenser, water was added thereto, and separated crystals were filtered, washed with water and dried. Crystals were collected and recrystallized from methanol to produce 2.31 g. of 2,3-dihydroxyimino- 5u-androst'an-17fl-ol which has a melting point of 262-- 263 C. (decomposition). [M +72.4 (in pyridine). U.V. max. 239-240 ma (6 6300) (in ethanol).
  • Example 5 A mixture of 2.0 g. of 2,3-dihydroxyimino-17a-methyl- 5a-androstan-17fl-ol, 0.5 g. of potassium hydroxide and 10 ml. of ethylene glycol was heated at a temperature After the resulting product was cooled, water was added thereto, and the separated product was filtered, washed with water and dried. The product was dissolved in benzene and passed through a column of alumina. The column was washed with ether, and the eluted fractions were collected and condensed. Subsequently, the residue was recrystallized from ether or aqueous methanol to produce 1.53 g.
  • Example 6 When 1.0 g. of sodium bicarbonate was used instead of 0.5 g. of potassium hydroxide in Example 5, 17,8-hydroxy- 17a-methyl- 50c tandrostano[2,3-C] furazan was obtained with 60% yield.
  • Example 8 A mixture of 0.2 g. of 2,3-dihydroxyimino-17ot methyl- 5a-androstan-l7fi-ol land 4 ml. of 5% aqueous solution of potassium hydroxide was heated under reflux for 10 hours. After the resulting batch was cooled, the separated product was filtered and thereafter treated in the same man ner as described in Example 5 to produce -hydroxy- 17a methyl 5a androstano[2,3-C]furazan with a 37% yield.
  • Example 9 A mixture of 1.37 g. of 2,3-dihydroxyimino-5a-tandrostan-17B-ol, 0.57 g. of potassium carbonate and 15 ml. of ethylene glycol was heated at a temperature between C. and C. for 30 minutes. The reaction mixture was condensed under reduced pressure, water was added thereto, and extraction was carried out with benzene. The benzene solution was washed with water, dried and passed through a column of alumina. The column was Washed with ether and the eluted fractions were collected and condensed. The residue was recrystallized from aqueous methanol to produce 0.84 g.
  • Example 12 0.19 g. of l7-acetate of 2,3-dihydroxyi-mino-Six-androstan-17B-ol was added to 30 ml. of liquid sulfur dioxide cooled to 10 C., then 0.12 g. of thionyl chloride was added dropwise thereto. After liquid sulfur dioxide was distilled off at room temperature, the residue was dissolved in chloroform and washed with sodium bicarbonate solution, then with water and dried. Chloroform was distilled off, and the residue was dissolved in benzene and purified by chromatography with the use of 3 g. of alumina. The fractions eluted with benzene-ether (9: 1) were collected and recrystallized from methanol to produce 0.115 g. of 17fl-acetoxy-5a-ahdrostano[2,3-C] furazan which has a melting point of 179 -180 C.
  • Example 14 In the same manner as described in Example 13, 0.62 g. of 17p-hydroxy-5a-androstano[2,3-C] furazan, 1.3 g. of propionic anhydride, and 10 ml. of pyridine were reacted to produce 0.61 g. of 17,6-propionyloxy-5a-androstano [2,3-C]furamn, which has a melting point of 136- 137 C. [a1 +43 (in chloroform).
  • Example 15 A mixture of 0.60 g. of 17B-hydroxy-5a-androstano[2, 3-C]furazan, 3 ml. of butyric anhydride, and 5 ml, of pyridine was heated at about 100 C. for 5 hours. After cooling, the reaction mixture was poured into water, and the separated product was filtered, washed with water, and dried. It was purified by chromatography on alumina and thereafter recrystallized from methanol to produce 0.62 g. of 17/3 n butyroyloxy 5a-androstano[2,3-C] furazan which has a melting point of 89 -90 C. [ah +41.6 (in chloroform).
  • Example 16 In the same manner as described in Example 15, 0.60 g. of l7fl-hydroxy-5a-androstano[2,3-C1furazan, 3 ml. of 3-phenylpropionic acid anhydride as an acylating agent, and 5 ml. of pyridine were reacted to produce 0.70 g. of 17 3 (3 phenylpropionyloxy) 5a androstan-o[2,3-C] furazan, which has a melting point of 1l0111 C, [aJ +45.7 (in chloroform).
  • Example 17 In the same manner as described in Example 15, 0.40 g. of l B-hydroxy-5a-androstano[2,3-C]furazan, 1.6 g. of n-heptanoic acid anhydride, and 5 ml. of pyridine were reacted to produce 0.37 g. of l7B-(n-heptanoyloxy)-5aF androstano[2,3-C1furazan, which has a melting point of 6566.5 C.
  • Example 18 A mixture of 0.20 g. of 17,8-hydroxy-5a-androstano[2, 3-C]furazan and 0.40 g. of n-heptanoic acid was heated at about C. for 2 hours. After the reaction mixture was cooled, water was added thereto, and the reaction mixture was neutralized with sodium carbonate. The separated product was filtered, washed with water, and purified by chromatography on alumina and thereafter recrystallized from ethanol to produce 17B-(n-heptanoyloxy)-5a-androstano[2,3-C]furazan with a 52% yield.
  • Example 19 In the same manner as described in Example 15, 0.50 g. of 17fl-hydroxy-5a-androstano[2,3-C]furazan, 3 g.- of n-decancic acid anhydride, and 10 ml. of pyridine were reacted to produce 0.57 g. of 17B-(n-decanoy1oxy)-5aandrostano[2,3-C1furazan, which has a melting point of 72-73.5 C.
  • Example 20 In the same manner as described in Example 20, 0.40 g. of 17B-hydroxy-5a-androstano[2,3-C1furazan, 1.0 g. of benzoyl chloride, and 6 ml. of pyridine were reacted to produce 0.4 g. of 17(3-benzoyloxy-5a-androstano[2,3-C] furazan, which has a melting point of 239241 C,
  • Example 22 A mixture of 0.33 g. of l7 8-hydr-oxy-l7a-methylandrostano[2,3-C]furazan, 8 ml. of acetic anhydride, and 2 ml, of pyridine was heated under reflux for an hour. Water was added, and the separated product was filtered,purified by alumina chromatography, and recrystallized from other to produce 0.19 g. of 17B-acetoxy-17a-methylandrostano [2,3-C1furazan, which has a melting point of 167- 168.5 C.
  • Example 23 0.33 g. of l7fi-hydroxy-17a-methylandrostano[2,3-C] furazan was dissolved in a mixture of 5 ml. of acetic acid and ml. of acetic anhydride, and 60 mg. of p-toluenesulfonic acid was added thereto. The reaction mixture was allowed to stand at room temperature for one and a half hours. Then, the reaction mixture was treated in the same manner as described in Example 22 to produce 0.15 g, of 17/3-acetoxy-17a-methylandrostano[2,3-C]furazan.
  • Example 24 Grignard reagent was prepared from ml. of ether, 72 mg. of magnesium, and 390 mg. of ethyl bromide. A solution of 0.33 g. of 17l3-hydroxy-17a-methylandrostano [2,3-C]furazan in 15 ml. of ether was added thereto, and the mixture was stirred. Then, a mixture of 0.31 g. of acetic anhydride and 5 ml. of ether was added thereto, and the resulting mixture was stirred at room temperature for 2.5 hours, then heated under reflux for 2 hours, and finally allowed to stand at room temperature for 16 hours. Water was added thereto, and the ether layer was separated, washed with water, and dried. Ether was distilled off, and the residue was purified by chromatography to produce 17B-acetoxy-17u-methylandrostano[2,3-C]furazan.
  • Example Grignard reagent was prepared from 20 ml. of ether, 120 mg. of magnesium and 0.71 g. of ethyl bromide, A solution of 0.66 g. of 17 8-hydroxy-l7ot-methylandrostano [2,3-C] furazan in 40 ml. of ether was added thereto. Then, a solution of 0.46 g. of propionyl chloride in 5 ml. of ether was added. After reflux for 3.5 hours, the reaction mixture was allowed to stand at room temperature for 16 hours. The mixture was then treated in the same manner as described in Example 24 to produce 0.41 g. of 175 propionyloxy 17e-methylandrostano[2,3-C]furazan, which has a melting point of 130.5131.5 C.
  • Example 26 Grignard reagent was prepared from 20 ml. of ether, 0.71 g. of ethyl bromide, and 0.21 g. of magnesium. A solution of 0.66 g. of 17,8-hydroxy-17a-methylandrostano [2,3-C1furazan in 40 ml. of ether was added thereto. Then, a solution of 0.84 g. of S-phenylpropionic acid chloride in 5 ml. of ether was added thereto. After reflux for 5 hours, the reaction mixture was allowed to stand at room temperature for 24 hours and then treated in the same manner as described in Example 24 to produce 0.56 g. of 17B-(3-phenylpropionyloxy)-17a-methylandrostano[2,3-C]furazan, which has a melting point of 165-166 C.
  • Example 27 In the same manner as described in Example 20, 0.30 g. of .7/3 (cyclohexylpropionyloxy)-5a-androstano[2,3-C] furazan was produced from 0.316 g. of l7fl-hydroxy-5aandrostano[2,3-C]furazan, 0.40 g. of cyclohexylpropionyl chloride, and 6 ml. of pyridine. The product was amorphous powder, which has a melting point of 115 l 17 C.
  • R is selected from the group consisting of hydro.- gen and the methyl group; R is selected from the group F consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 16 carbon atoms.
  • H0-N I H ON wherein R is defined as above.
  • R" in the former formula representing COCH CH COOH when R is hydrogen and succinic anhydride is vused as a dehydrating agent, and the same acyl group as R" when R is the acyl group defined as above.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US350585A 1963-04-10 1964-03-09 Steroid [2, 3-c] furazan compounds and the process for the production thereof Expired - Lifetime US3245988A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP1886763 1963-04-10
JP3845663 1963-07-15
JP6546563 1963-12-05
JP728364 1964-02-12

Publications (1)

Publication Number Publication Date
US3245988A true US3245988A (en) 1966-04-12

Family

ID=27454691

Family Applications (1)

Application Number Title Priority Date Filing Date
US350585A Expired - Lifetime US3245988A (en) 1963-04-10 1964-03-09 Steroid [2, 3-c] furazan compounds and the process for the production thereof

Country Status (8)

Country Link
US (1) US3245988A (en(2012))
BE (1) BE645743A (en(2012))
BR (1) BR6458290D0 (en(2012))
CH (1) CH443285A (en(2012))
DE (1) DE1230795B (en(2012))
FR (1) FR4729M (en(2012))
GB (1) GB1018780A (en(2012))
NL (2) NL6402929A (en(2012))

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332941A (en) * 1965-06-01 1967-07-25 Daiichi Seiyaku Company Ltd 17-ether compounds of 17beta-hydroxy-5alpha-androstano[2, 3-c] furazan
US3415818A (en) * 1965-07-08 1968-12-10 Sterling Drug Inc Dioximidoandrostanes and cyclized n-oxides derived therefrom

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332941A (en) * 1965-06-01 1967-07-25 Daiichi Seiyaku Company Ltd 17-ether compounds of 17beta-hydroxy-5alpha-androstano[2, 3-c] furazan
US3415818A (en) * 1965-07-08 1968-12-10 Sterling Drug Inc Dioximidoandrostanes and cyclized n-oxides derived therefrom

Also Published As

Publication number Publication date
BE645743A (en(2012)) 1964-07-16
GB1018780A (en) 1966-02-02
BR6458290D0 (pt) 1973-08-28
DE1230795B (de) 1966-12-22
CH443285A (fr) 1967-09-15
NL6402929A (en(2012)) 1964-10-12
FR4729M (en(2012)) 1967-01-09
NL126394C (en(2012))

Similar Documents

Publication Publication Date Title
US3166577A (en) 1, 2-dimethyl estrogens and intermediates used in the production thereof
US3691215A (en) The preparation of 7alpha-methyl-delta4,9,11-estratrienes
US3325520A (en) (optionally 17-hydrocarbon-substituted) 11, 13beta-dialkylgon-4-en-3-ones and esters corresponding
US3245988A (en) Steroid [2, 3-c] furazan compounds and the process for the production thereof
US2883424A (en) Dihydroxy steroid derivatives and method of preparing same
US3210406A (en) A-norandrostenes and preparation thereof
US2963498A (en) Dehydro derivatives of 11-oxygenated 17alpha-(lower alkanoyl)-oxy-9alpha-halopregnane-3, 20-diones
US2713061A (en) 3-methyl androstanes
US3079408A (en) Ig-bisoxygenated iy-haloestra-
US3636011A (en) 11beta-fluoro-19-nor-steroids and process for their preparation
US3471526A (en) (optionally 17-alkylated) 1beta-methyl-5alpha-androstane-1alpha,17beta-diols,delta**2 derivatives corresponding and esters thereof
US3096350A (en) 6, 16alpha-dimethyl-delta1, 4, 6-pregnatriene-17alpha-ol-3, 20-dione and esters thereof
US3270008A (en) Novel process for 3-oxo-delta4, 6 steroids
US3391168A (en) 1, 17-dimethyl-5-androstane-3beta, 17beta-diol and esters thereof
US3203966A (en) 17alpha-(hydrocarbon-substituted)-5alpha-androst-2-en-17beta-ols and esters thereof
US3166578A (en) (optionally 17-alkylated) 17-oxygenated 5alpha-androst-2-en-4-ones and intermediatesthereto
US3080399A (en) Cyclopentanophenanthrene compounds and process
US2683712A (en) Steroid alkali-metal enolates
US3257428A (en) 1, 17-dioxygenated 5alpha-androstanes and delta analogs
US3032565A (en) Process for the manufacture of 6-alkoxy-and 6-keto steroids and compounds obtained thereby
US2588396A (en) Pyrolysis of steroid products
US3144447A (en) Pyrazolo-androstanes
US3716559A (en) 4-methylen-2-oxa-3-keto androstanes and 4-methyl-delta4 derivatives thereof
US2921064A (en) 6, 7-dihydroxy estradiol and intermediates thereof
US3013028A (en) Esters of optionally 17-alkylated androsta-4,6-diene 3beta, 17beta-diols and intermediates thereto